Many medical intravascular devices are currently being used either temporarily or permanently inside the human body to address conditions associated with cardiovascular disease, high blood pressure, diabetes, and stroke. One example of an intravascular device is a stent for use in, for instance, coronary angioplasty. Stents are small mechanical devices that can be implanted within a vascular structure, such as a blood vessel or an artery, and can be self or mechanically expanded to maintain an open lumen at a constricted location to permit a substantially clear flow path therethrough. A stent can also act to support a vessel wall in areas vulnerable to collapse. Stents can carry drug that is eluted or slowly released to treat or stabilize the vessel (DES-Drug Eluting Stents).
The mechanical reopening of a constricted vessel can sometimes lead to injuries of the tissues at the site of constriction or closure. Such injuries can often stimulate thrombus formation at such a site, as well as release of tissue debris that may subsequently act to block fluid flow within the vessel. Moreover, if permitted to proliferate, pronounced neointimal hyperplasia or restenosis can result. Furthermore, stent scaffolding cause uneven (unsmooth) vessel structure and the properties of the present metals and alloys stent structure add to the restenosis process and lower their long term efficacy. Thrombus production remains one of the most common post-stenting clinical problem, and requires effective intervention or counter-measures to prevent and/or control its reoccurrence.
Currently, methods for preventing or controlling thrombus are specifically aimed at influencing factors believed to be involved in the body's response to external or internal tissue stimulants, such as angioplasty, stenting procedures, biofilms and/or viruses. Common countermeasures which have been used to prevent or control restenosis generally fall into the one of several categories, including (1) mechanical atheroablative techniques, such as debulking, vascular filters, and emboli-trapping devices, (2) ultrasound-initiated atheroablative techniques, (3) light-assisted procedures, predominantly excimer laser angioplasty, (4) pharmacological agents and gene therapy, (5) ultraviolet photophoresis, believed to be an immune modulator, (6) radiation therapy, such as external and endovascular brachytherapy, and (7) re-stenting.
In addition, modifications to stent designs and materials have been proposed to prevent and/or control restenosis. In one approach, non-metallic, biodegradable stent materials, such as high molecular weight Poly-l-lactic acid (PLLA) is used.
Numerous inorganic coatings and surface treatments have also been developed to improve chemical inertness and biocompatibility of metallic stents. Some coatings, such as gold, however, yield a higher rate of in-stent restenosis than uncoated stents. Others, including silicon carbide and turbostatic carbon, show promise but additional studies must be done.
Organic coatings, including both synthetic and natural coatings, have also been widely studied. Among the synthetic coatings studied are Dacron, polyester, polyurethane, polytetrafluoroethylene (PTFE), polyethylacrylate/polymethylmetha-crylate, polyvinyl chloride, silicone, collagen, and iridium oxide. Results of studies, such as those with PTFE-coated stents, are disappointing or mixed at best, as there are high occurrences of late thrombo-occlusive events. With only a very few exceptions, the general consensus is that any favorable outcome was not associated with treatment of conventional in-stent restenosis using PTFE-coated stents.
Intracoronary intervention has also been employed to reduce neointima formation by reducing smooth muscle cell proliferation after balloon angioplasty. However, such intervention is often complicated by subacute and late thrombosis. Coronary thrombo-aspdrugiration and coronary pulsed-spray procedures, followed by immediate endovascular therapy, have also been particularly helpful in removing thrombotic material associated with plaque.
In addition, pharmacotherapeutic agents have been used for the treatment of some of the major post-angioplasty complications, including immunosuppresants, anticoagulants and anti-inflammatory compounds, chemotherapy agents, antibiotics, antiallergenic drugs, cell cycle inhibitors, gene therapy compounds, and ceramide therapy compounds. Pharmacotherapeutic agents can be delivered either systemically or locally. Systemic treatment has shown limited success in reducing restenosis following stent implantation, a result believed to be due to inadequate concentration of the pharmacotherapeutic agents at the site of injury. Increased dose administration, however, is constrained by possible systemic toxicity. It has been observed that local delivery of higher doses via drug eluting stents can significantly reduce adverse systemic effects. However, the local delivery of drugs via stents may be limited by the amount of surface area for drug elution.
Gene therapy has also been employed in the treatment of thrombus production. The procedure is directed towards smooth muscle cells and involves gene transfer via DNA, with or without integration of chromosomes, into selected cells. In transduction without integration, the gene is delivered to both cytoplasm and nucleus and is therefore non-selective. Gene transfer for integration employs retrovirus to affect growth stimulators.
Antibiotics, likewise, has been used in the treatment of coronary artery disease. It is known that antibiotics are effective in controlling inflammation caused by a variety of infectious agents found in fatty plaques blocking the arteries. Results of clinical investigation, such as with azithromycin, suggest a modest antibiotic benefits for heart patients.
Similarly, a phospholipid exhibiting immunosuppressive properties has been shown to block T-cell activation and proliferation, inhibit Taxol-induced cell cycle apoptosis, and activate protein kinase signal translation in malignant myogenic cells. Rapamycin and its analogs exhibit anti-tumor activities at relatively low dose levels, while inducing only mild side effects, an extremely important aspect of patient care.